title: SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients.
abstract: We analyzed a large cohort of 1160 untreated CLL patients for novel genetic markers (SF3B1, NOTCH1, FBXW7, MYD88, XPO1) in the context of molecular, immunophenotypic and cytogenetic data. NOTCH1 mutations (mut) (12.3%), SF3B1mut (9.0%) and TP53mut (7.1%) were more frequent than XPO1mut (3.4%), FBXW7mut (2.5%) and MYD88mut (1.5%). SF3B1mut, NOTCH1mut, TP53mut and XPO1mut were highly correlated to unmutated, whereas MYD88mut were associated with mutated IGHV status. Associations of diverse cytogenetic aberrations and mutations emerged: (1) SF3B1mut with del(11q), (2) NOTCH1mut and FBXW7mut with trisomy 12 and nearly exclusiveness of SF3B1mut, (3) MYD88mut with del(13q) sole and low frequencies of SF3B1mut, NOTCH1mut and FBXW7mut. In patients with normal karyotype only SF3B1mut were frequent, whereas NOTCH1mut rarely occurred. An adverse prognostic impact on time to treatment (TTT) and overall survival (OS) was observed for SF3B1mut, NOTCH1mut and TP53 disruption. In multivariate analyses SF3B1mut, IGHV mutational status and del(11q) were the only independent genetic markers for TTT, whereas for OS SF3B1mut, IGHV mutational status and TP53 disruption presented with significant impact. Finally, our data suggest that analysis of gene mutations refines the risk stratification of cytogenetic prognostic subgroups and confirms data of a recently proposed model integrating molecular and cytogenetic data.
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Jeromin
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Weissmann
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Haferlach
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Dicker
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Bayer
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Grossmann
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Alpermann
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Roller
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kohlmann
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Kern
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schnittger
mesh_terms: D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006801:Humans; D016130:Immunophenotyping; D028884:Karyopherins / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D011379:Prognosis; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1 / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D000097606:Exportin 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D028884:Karyopherins; D053594:Myeloid Differentiation Factor 88; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1; D018160:Receptors, Cytoplasmic and Nuclear; D017413:Ribonucleoprotein, U2 Small Nuclear; D044767:Ubiquitin-Protein Ligases; D000097606:Exportin 1 Protein; C513273:FBXW7 protein, human; C507779:MYD88 protein, human; C497761:NOTCH1 protein, human; C112491:SF3B1 protein, human